Process for producing cyclic compound

ABSTRACT

A process suitable for safely mass-producing, through a short step, cyclic compounds useful in medicines, agricultural chemicals, foods, cosmetics, and chemical products or as intermediates therefor. The process, which is for producing a compound represented by the formula:  
                 
 
     {wherein Z represents an electron-attracting group; W represents optionally substituted ethylene or optionally substituted vinylene; R 3  represents hydrogen or an optionally substituted hydrocarbon group; and X represents a divalent group [provided that when W represents optionally substituted vinylene, then —X—CH 2 —Z is not —X 1 —X 2 —CH 2 —Z (wherein X 1  represents sulfur or optionally substituted nitrogen and X 2  represents optionally substituted ethylene)]} or a salt thereof, is characterized by subjecting a compound represented by the formula (II) or a salt thereof:  
                 
 
     (wherein the symbols have the same meanings as the above) to a ring closure reaction in a solvent containing a carbonic diester.

TECHNICAL FIELD

[0001] The present invention relates to a process for producing cycliccompounds useful as medicines, agricultural chemicals, foods, cosmeticsand chemical products, or intermediates thereof.

BACKGROUND ART

[0002] Heretofore, several synthetic methods for cyclic compounds havebeen described in literature, including, for example, (1) anintramolecular Friedel-Crafts Reaction in the case of cyclic ketonederivatives (JP-A 57-192379, etc.), (2) a Dieckmann-type cyclizationreaction of diester derivatives, followed by reduction and dehydrationreactions in the case of cyclic acrylic acid derivatives (J. Chem. Res.,Synop., (1987), (12), 394-5, etc.), (3) an intramolecular WittigReaction in the case of cyclic alkene derivatives (WO98/55475, etc.) andothers.

[0003] However, even though a variety of useful intermediates have beendescribed, for example, in J. Heterocyclic Chem., 31, 351-355 (1994),Heterocycles, 49, 215-232 (1998), J. Heterocyclic Chem., 33, 1909-1913(1996), etc., cyclic compounds (especially, cyclic compounds having 8-or more-membered ring ) are still generally difficult to synthesize andcan be obtained only at low yields even if possible.

[0004] From the current situation as described above, it is desirable toestablish a convenient production method (i.e., a production methodwhich employs readily available low-cost raw materials, and reagentssuitable for large scale synthesis and having no disposal problems, andwhich comprises relatively short steps and is easier to carry out), ofcyclic compounds, especially cyclic alkene derivatives, which can beeasily converted to a variety of derivatives including, e.g., cyclicketone derivatives or cyclic acrylic acid derivatives, due to theircharacteristic chemical structure.

DISCLOSURE OF INVENTION

[0005] As a result of intensive studies, the present inventors foundthat a cyclic alkene derivative can be produced inexpensively andconveniently by using an activated methylene derivative as a reactionintermediate and by conducting a cyclization reaction in the presence ofa carbonic diester, and on the basis of this knowledge, after furtherstudies, completed the present invention.

[0006] That is, the present invention provides

[0007] (1) A process for producing a compound represented by theformula:

[0008] [wherein, Z is an electron-withdrawing group; W is an optionallysubstituted ethylene or an optionally substituted vinylene, and when theethylene or the vinylene has two substituent groups, said substituentgroups may be bound to each other to form an optionally substitutedcyclic ring; R³ is a hydrogen atom or an optionally substitutedhydrocarbon group ; and X is a divalent group (preferably, a divalentgroup having 3 or more atoms in the straight-chain moiety thereof)(however, when W is an optionally substituted vinylene, —X—CH₂—Z is not—X¹—X²—CH₂—Z (wherein, X¹ is a sulfur atom or an optionally substitutednitrogen atom, X² is an optionally substituted ethylene))] or a saltthereof, which comprises subjecting a compound represented by theformula:

[0009] [wherein, each symbol has the same meaning described as above] ora salt thereof to a cyclization reaction in a solvent containing acarbonic diester;

[0010] (2) The process according to the above-mentioned (1), wherein Xis a divalent group having 1 to 12 atoms in the straight-chain moietythereof (preferably, 3 to 12 atoms in the straight-chain moietythereof);

[0011] (3) The process according to the above-mentioned (1), wherein Zis a carboxyl group which is esterified;

[0012] (4) The process according to the above-mentioned (1), wherein R³is a hydrogen atom;

[0013] (5) The process according to the above-mentioned (1), whichcomprises the reaction being carried out in the presence of a base;

[0014] (6) The process according to the above-mentioned (5), wherein thebase is an alcoholate;

[0015] (7) The process for producing a compound represented by theformula:

[0016] [wherein, Z is an electron-withdrawing group; R¹ and R² each area hydrogen atom, a halogen atom, an optionally substituted amino group,an optionally substituted hydroxy group, an optionally substituted thiolgroup, an optionally substituted hydrocarbon group, or an optionallysubstituted heterocyclic; R¹ and R² may be bound to each other to forman optionally substituted ring; R³ is a hydrogen atom or an optionallysubstituted hydrocarbon group; the combined line of a broken line and asolid line is a single bond or a double bond; and X is a divalent group(preferably, a divalent group having 3 or more atoms in thestraight-chain moiety thereof) (however, when the combined line of abroken line and a solid line is a double bond, —X—CH₂—Z is not—X¹—X²—CH₂—Z ( wherein , X¹ is a sulfur atom or an optionallysubstituted nitrogen atom, X² is an optionally substituted ethylene))]or a salt thereof, which comprises subjecting a compound represented bythe formula:

[0017] [wherein, each symbol has the same meaning described as above] ora salt thereof to a cyclization reaction in a solvent containing acarbonic diester;

[0018] (8) The process according to the above-mentioned (7), wherein Xis a divalent group having 1 to 12 atoms in the straight-chain moietythereof (preferably, 3 to 12 atoms in the straight-chain moietythereof);

[0019] (9) The process according to the above-mentioned (7), wherein Zis a carboxyl group which is esterified;

[0020] (10) The process according to the above-mentioned (7), wherein R³is a hydrogen atom;

[0021] (11) The process according to the above-mentioned (7), whichcomprises the reaction being carried out in the presence of a base;

[0022] (12) The process according to the above-mentioned (11), whereinthe base is an alcoholate;

[0023] (13) The process for producing a compound represented by theformula:

[0024] [wherein, Z is an electron-withdrawing group; R³ is a hydrogenatom or an optionally substituted hydrocarbon group; the combined lineof a broken line and a solid line is a single bond or a double bond;ring A is an optionally substituted ring; and X is a divalent group(preferably, a divalent group having 3 or more atoms in thestraight-chain moiety thereof) (however, when the ring A is anoptionally substituted benzene ring and the combined line of a brokenline and a solid line is a double bond, —X—CH₂—Z is not —X¹—X²—CH₂—Z(wherein, X¹ is sulfur atom or an optionally substituted nitrogen atom ;X² is an optionally substituted ethylene))] or a salt thereof, whichcomprises subjecting a compound represented by the formula:

[0025] [wherein, each symbol has the same meaning described as above] ora salt thereof to a cyclization reaction in a solvent containing acarbonic diester;

[0026] (14) The process according to the above-mentioned (13), wherein Xis a divalent group having 1 to 12 atoms in the straight-chain moietythereof (preferably, 3 to 12 atoms in the straight-chain moietythereof);

[0027] (15) The process according to the above-mentioned (13), wherein Zis a carboxyl group which is esterified;

[0028] (16) The process according to the above-mentioned (13), whereinR³ is a hydrogen atom;

[0029] (17) The process according to the above-mentioned (13), whichcomprises the reaction being carried out in the presence of a base;

[0030] (18) The process according to the above-mentioned (17), whereinthe base is an alcoholate;

[0031] (19) The compound represented by the formula:

[0032] [wherein, Z is an electron-withdrawing group; W is an optionallysubstituted ethylene or an optionally substituted vinylene, and when theethylene or the vinylene has two substituent groups, said substituentgroups may be bound to each other to form an optionally substitutedring; R³ is a hydrogen atom or an optionally substituted hydrocarbongroup; and X″ is a divalent group having 4 or more atoms in thestraight-chain moiety thereof] or a salt thereof;

[0033] (20) The compound according to the above-mentioned (19), whereinX″ is a divalent group having 4 to 6 atoms in the straight-chain moietythereof;

[0034] (21) The compound according to the above-mentioned (19), whereinZ is a carboxyl group which is esterified;

[0035] (22) The compound according to the above-mentioned (19), whereinR³ is a hydrogen atom;

[0036] (23) The compound represented by the formula:

[0037] [wherein, Z is an electron-withdrawing group; R¹ and R² each area hydrogen atom, a halogen atom, an optionally substituted amino group,an optionally substituted hydroxy group, an optionally substituted thiolgroup, an optionally substituted hydrocarbon group or an optionallysubstituted heterocyclic group; R¹ and R² may be bound to each other toform an optionally substituted ring; R³ is a hydrogen atom or anoptionally substituted hydrocarbon group; the combined line of a brokenline and a solid line is a single bond or a double bond; and X″ is adivalent group having 4 or more atoms in the straight-chain moietythereof] or a salt thereof;

[0038] (24) The compound according to the above-mentioned (23), whereinX″ is a divalent group having 4 to 6 atoms in the straight-chain moietythereof;

[0039] (25) The compound according to the above-mentioned (23), whereinZ is a carboxyl group which is esterified;

[0040] (26) The compound according to the above-mentioned (23), whereinR³ is a hydrogen atom;

[0041] (27) The compound represented by the formula:

[0042] [wherein, Z is an electron-withdrawing group; R³ is a hydrogenatom or an optionally substituted hydrocarbon group; the combined lineof a broken line and a solid line is a single bond or a double bond;ring A is an optionally substituted ring; and X″ is a divalent grouphaving 4 or more atoms in the straight-chain moiety thereof] or a saltthereof;

[0043] (28) The compound according to the above-mentioned (27), whereinX″ is a divalent group having 4 to 6 atoms in the straight-chain moietythereof;

[0044] (29) The compound according to the above-mentioned (27), whereinZ is a carboxyl group which is esterified; and

[0045] (30) The compound according to the above-mentioned (27), whereinR³ is a hydrogen atom; and the like.

[0046] Examples of “electron-withdrawing group” used in the presentspecification include (i) a carboxyl group which may be optionallyesterified or amidated, (ii) a group represented by the formula: —(CO)R⁴(wherein, R⁴ is a hydrogen atom or an optionally substituted hydrocarbongroup), (iii) nitrile group, (iv) nitro group, (v) a group representedby the formula: —(SO_(m))R⁵ (wherein, m is an integer of 1 or 2, and R⁵is an optionally substituted hydrocarbon group), (vi) a grouprepresented by the formula: —PR⁶ R⁷ (wherein, R⁶ and R⁷ each are anoptionally substituted hydrocarbon group), (vii) a group represented bythe formula: —(PO) (OR⁸) (OR⁹) (wherein, R⁸ and R⁹ each are a hydrogenor an optionally substituted hydrocarbon group), (viii) an optionallysubstituted aryl group, (ix) an optionally substituted alkenyl group,(x) a halogen atom ( e.g., fluorine, chlorine, bromine, iodine, etc.)and (xi) a nitroso group and the like, preferably, a carboxyl groupwhich may be optionally esterified or amidated, a group represented bythe formula: —(CO)R⁴, nitrile group, nitro group, a group represented bythe formula: —(SO_(m))R⁵, a group represented by the formula: —PR⁶ R⁷, agroup represented by the formula: —(PO) (OR⁸) (OR⁹), more preferably, acarboxyl group which is esterified (e.g., a carboxyl group which isesterified by a C₁₋₄ alkyl such as methoxycarbonyl, ethoxycarbonyl,t-butoxycarbonyl, etc.) and the like.

[0047] The “carboxyl group which is esterified” in the “carboxyl groupwhich may be optionally esterified or amidated” of (i) above include agroup represented by the formula: —(CO)OR¹⁰ (wherein, R¹⁰ is anoptionally substituted hydrocarbon group), while the “carboxyl groupwhich is amidated” include a group represented by the formula: —(CO)NR¹¹R¹² (wherein, R¹¹ and R¹² are, respectively, a hydrogen atom or anoptionally substituted hydrocarbon group, and R¹¹ and R¹² may be boundto each other to form a 5- to 7-membered (preferably, 5- to 6-membered)cyclic amino group together with a neighboring nitrogen atom (e.g.,tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine,pyrrole, imidazole, etc.)).

[0048] Further, in the formula of (vi) or (vii) above, R⁶ and R⁷, or R⁸and R⁹ may be bound to each other to form, for example, a lower (C₂₋₆)alkylene (e.g., dimethylene, trimethylene, tetramethylene, etc.), alower (C₂₋₆) alkenylene (e.g., —CH₂—CH═CH—, —CH₂—CH₂—CH═CH—,—CH₂—CH═CH—CH₂—, etc.), or a lower (C₄₋₆) alkadienylene (e.g.,—CH═CH—CH═CH—, etc.), etc., preferably, a lower (C₁₋₆) alkylene, morepreferably, a lower (C₂₋₄) alkylene, and these divalent groups may haveoptionally substituent groups including, for example, hydroxy group, ahalogen atom, a C₁₋₄ alkyl, a C₁₋₄ alkoxy, etc.

[0049] Examples of the “aryl group” in the optionally substituted arylgroup of (viii) above include, for example, C₆₋₁₄ aryl groups such asphenyl, naphthyl, etc., preferably, C₆₋₁₀ aryl groups, etc., morepreferably, phenyl, etc. The aryl group may have 1 to 3 substituentgroups similar to those of the “optionally substituted hydrocarbongroup” described below.

[0050] The “alkenyl groups” in the optionally substituted alkenyl groupof (ix) above include, for example, alkenyl groups having 2 to 10 carbonatoms such as vinyl, allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., and thelike, preferably, lower (C₂₋₆) alkenyl groups, etc., more preferably,vinyl, etc. The alkenyl group may have 1 to 3 substituent groups similarto those of the “optionally substituted hydrocarbon group” describedbelow.

[0051] Examples of the “hydrocarbon group” in the “optionallysubstituted hydrocarbon group” used in the present specificationinclude;

[0052] (1) an alkyl group (e.g., C₁₋₁₀ alkyl groups such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.,preferably, lower (C₁₋₆) alkyl groups, etc.);

[0053] (2) a cycloalkyl group (e.g., C₃₋₇ cycloalkyl groups such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and thelike);

[0054] (3) an alkenyl group (e.g., alkenyl groups having 2 to 10 carbonatoms such as vinyl, allyl, crotyl, 2-pentenyl, 3-hexenyl, etc.,preferably, lower (C₂₋₆) alkenyl groups, etc.);

[0055] (4) a cycloalkenyl group (e.g., cycloalkenyl groups having 3 to 7carbon atoms such as 2-cyclopentenyl, 2-cyclohexenyl,2-cyclopentenylmethyl, 2-cyclohexenylmethyl and the like);

[0056] (5) an alkynyl group (e.g., alkynyl groups having 2 to 10 carbonatoms such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-pentynyl,3-hexynyl, etc., preferably, lower (C₂₋₆) alkynyl groups and the like);

[0057] (6) an aryl group (e.g., C₆₋₁₄ aryl groups such as phenyl,naphthyl, etc., preferably, C₆₋₁₀ aryl groups, more preferably, phenyl,etc.); and

[0058] (7) an aralkyl group (e.g., phenyl-C₁₋₄ alkyl groups (e.g.,benzyl, phenethyl, etc.) and the like). The examples of the hydrocarbongroups are preferably, an alkyl group, more preferably, a C₁₋₄ alkylgroup such as methyl, ethyl, etc., and particularly preferably, methyl.

[0059] Said hydrocarbon group may have substituent groups, including,for example, a halogen atom (e.g., fluorine, chlorine, bromine, iodine,etc.), nitro, cyano, hydroxy, an optionally substituted thiol group(e.g., thiol, C₁₋₄ alkylthio, etc.), an optionally substituted aminogroup (e.g., amino, monoC₁₋₄ alkylamino, diC₁₋₄alkylamino, 5- to6-membered cyclic amino groups such as tetrahydropyrrole, piperazine,piperidine, morpholine, thiomorpholine, pyrrole, imidazole and thelike), a carboxyl group which may be optionally esterified or amidated(e.g., carboxyl, C₁₋₄ alkoxycarbonyl, carbamoyl, monoC₁₋₄alkylcarbamoyl,diC₁₋₄ alkylcarbamoyl, etc.), a C₁₋₄ alkyl group which may be optionallysubstituted with halogen atoms or C₁₋₄ alkoxy groups (e.g.,trifluoromethyl, methyl, ethyl, etc.), a C₁₋₄ alkoxy group which may beoptionally substituted with halogen atoms or C₁₋₄ alkoxy groups (e.g.,methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, aC₂₋₄ alkanoyl group (e.g., acetyl, propionyl, etc.), a C₁₋₄alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl, etc.), and aC₁₋₄ alkylsulfinyl (e.g., methanesulfinyl, ethanesulfinyl, etc.). Thenumber of the substituent groups is preferably 1 to 3.

[0060] In the formula above, the “ethylene” and the “vinylene” in the“optionally substituted ethylene” and the “optionally substitutedvinylene” represented by W include divalent groups represented by theformula: —CH₂—CH₂— and the formula: —CH═CH—. These divalent groups mayhave substituent groups at any position where substitution is possible,and examples thereof include substituent groups similar to those of “ahalogen atom”, “an optionally substituted amino group”, “an optionallysubstituted hydroxy group”, “an optionally substituted thiol group”, “anoptionally substituted hydrocarbon group” and “an optionally substitutedheterocyclic group” represented by R¹ and R² described below. When theethylene or the vinylene has two substituent groups, the substituentgroups may be bound to each other to form an optionally substitutedring. Further, R¹ and R² may be bound to each other to form anoptionally substituted ring. Here, examples of the optionallysubstituted ring are those similar to an optionally substituted ring asring A described below (preferably, an optionally substituted benzenering and the like).

[0061] Examples of the “halogen atom” represented by R¹ and R² in theformula above include fluorine, chlorine, bromine, iodine, etc.

[0062] Examples of the “optionally substituted amino group” representedby R¹ and R² in the formula above include amino groups which may beoptionally substituted by the “optionally substituted hydrocarbongroups” mentioned above. The number of substituent groups may be any of0 to 2. When two substituent groups are present, the two substituentgroups may be the same or different. Further, the two substituent groupsmay be bound to each other to form a 5- to 7-membered (preferably, 5- to6-membered) cyclic amino group together with neighboring nitrogen atoms(e.g., tetrahydropyrrole, piperazine, piperidine, morpholine,thiomorpholine, pyrrole, imidazole, etc.).

[0063] Examples of the “optionally substituted hydroxy group”represented by R¹ and R² in the formula above include hydroxy groupswhich may be optionally substituted by the “optionally substitutedhydrocarbon groups” mentioned above.

[0064] Examples of “the optionally substituted thiol group” representedby R¹ and R² in the formula above include thiol groups which may beoptionally substituted by the “optionally substituted hydrocarbongroups” mentioned above.

[0065] In the formula above, examples of the “heterocyclic ring” in the“optionally substituted heterocyclic group” represented by R¹ and R²,include 5- to 7-memberd aromatic heterocyclic rings and saturated orunsaturated non-aromatic heterocyclic rings (aliphatic heterocyclicrings), containing at least one (preferably, 1 to 4, more preferably 1to 2) hetero atoms of 1 to 3 (preferably, 1 to 2) hetero atoms selectedfrom the group consisting of oxygen atom, sulfur atom, nitrogen atom andother atoms.

[0066] Herein, examples of the “aromatic heterocyclic ring” include 5-to 6-membered aromatic monocyclic heterocyclic rings (e.g., furan,thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole,imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole,1,3,4-oxadiazole, furazan, 1,2,3-thiadiazole, 1,2,4-thiadiazole,1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine,pyridazine, pyrimidine, pyrazine, triazine, etc.). Examples of the“non-aromatic heterocyclic ring” include 5- to 7-membered (preferably,5- to 6-membered) saturated or unsaturated (preferably, saturated)non-aromatic heterocyclic rings (aliphatic heterocyclic rings) such aspyrrolidine, tetrahydrofuran, thiolane, piperidine, tetrahydropyran,morpholine, thiomorpholine, piperazine, pyran, etc., and 5- to6-membered non-aromatic heterocyclic rings wherein all or a part ofdouble bonds in the afore-mentioned aromatic monocyclic heterocyclicrings are saturated. The heterocyclic ring is preferably a 5- to6-membered aromatic ring, and more preferably furan, thiophene, pyrrole,or pyridine (preferably a 6-membered ring).

[0067] Examples of substituent groups which may be possessed by theheterocyclic ring include substituent groups exemplified as thesubstituent groups on the “optionally substituted hydrocarbon group”described above, and the number of the substituent groups is 1 to 3.

[0068] In the formula above, Z is preferably an esterified carboxylgroup, R³ is preferably a hydrogen atom, and R¹ and R² each ispreferably a hydrogen atom or an optionally. substituted hydrocarbongroup, more preferably a hydrogen atom, and it is also preferable thatR¹ and R² are bound to each other to form an optionally substitutedbenzene ring.

[0069] The substituent groups which may be possessed by the “optionallysubstituted benzene ring” used in the present specification includesubstituent groups exemplified as the substituent groups on the“optionally substituted hydrocarbon group” described above; theafore-described “optionally substituted aryl groups”, which may be boundvia a spacer (e.g., a divalent group having 1 to 4 atoms in thestraight-chain moiety thereof) (preferably, afore-described “optionallysubstituted aryl groups which is directly bound), and particularlypreferably electron-donating groups. The number of the substituentgroups is 1 to 4.

[0070] Examples of the “spacer” are —(CH₂)_(a)— [a is an integer of 1 to4 (preferably, an integer of 1 to 2)], —(CH₂)_(b)—X′— [b is an integerof 0 to 3 (preferably, an integer of 0 to 1), X′ is an optionallysubstituted imino group (e.g., imino groups which may be substitutedwith lower (C₁₋₆) alkyl, lower (C₃₋₇) cycloalkyl, formyl, lower (C₂₋₇)alkanoyl, lower (C₁₋₆) alkoxy-carbonyl etc.), a carbonyl group, anoxygen atom or an optionally oxidized sulfur atom (e.g., —S(O)_(n)— (nis an integer of 0 to 2))], —CH═CH—, —C≡C—, —CO—NH—, —SO₂—NH— etc.(preferably —(CH₂)_(b)—X′—, more preferably —CH₂—O—). These groups maybe bound to the “optionally substituted benzene ring” via either theright or left bond, but they are bound to the “optionally substitutedbenzene ring” preferably via the right bond.

[0071] Examples of the ring formed by binding R¹ and R² and the“optionally substituted ring” represented by A in the formula aboveinclude 5- to 7-membered (preferably, 5- to 6-membered) saturated orunsaturated alicyclic hydrocarbons such as C₅₋₇ cycloalkanes (e.g.,cyclopentane, cyclohexane, cycloheptane, etc.), C₅₋₇ cycloalkenes (e.g.,1-cyclopentene, 2-cyclopentene, 3- cyclopentene, 2-cylcohexene,3-cylcohexene, etc.), and C₅₋₆ cycloalkadienes (e.g.,2,4-cyclopentadiene, 2,4-cyclohexadiene, 2,5-cyclohexadiene, etc); 6- to14-membered aromatic hydrocarbons such as benzene, naphthalene, azulene,acenaphthylene, etc.; and 5- to 7-memberd aromatic heterocyclic ringsand saturated or unsaturated non-aromatic heterocyclic rings (aliphaticheterocyclic rings) containing at least one (preferably, 1 to 4, morepreferably 1 to 2) hetero atoms of 1 to 3 (preferably, 1 to 2) heteroatoms selected from the group consisting of oxygen atom, sulfur atom,nitrogen atom and other atoms.

[0072] Examples of the “aromatic heterocyclic ring” include 5- to6-membered aromatic monocyclic heterocyclic rings (e.g., furan,thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole,imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,3-thiadiazole,1,2,3-triazole, pyridine, pyridazine, pyrimidine, pyrazine, etc.), andexamples of the “non-aromatic heterocyclic ring” include 5- to7-membered (preferably 5- to 6-membered) saturated or unsaturatednon-aromatic monocyclic heterocyclic rings (aliphatic heterocyclicrings) such as pyrrolidine, tetrahydrofuran, thiolane, piperidine,morpholine, thiomorpholine, tetrahydropyran, piperazine, pyran etc., or5- to 6-membered non-aromatic heterocyclic rings wherein all or a partof the double bonds in the afore-described aromatic monocyclicheterocyclic rings are saturated.

[0073] Further, the ring formed by binding R¹ and R², and the“optionally substituted ring” represented by A in the formula above mayform a fused ring wherein 2 to 3 (preferably, 2) monocyclic ringsdescribed above are condensed. Preferable examples of the fused ringinclude fused rings of two same or different heterocyclic rings(preferably, one heterocyclic ring and one aromatic heterocyclic ring,more preferably, two same or different aromatic heterocyclic rings); andfused rings of a heterocyclic ring and a homocyclic ring (preferably, aheterocyclic ring and a benzene ring, more preferably, an aromaticheterocyclic ring and a benzene ring). Specific examples of the fusedring include indole, benzothiophene, benzofuran, benzimidazole,imidazo[1,2-a]pyridine, quinoline, isoquinoline, cinnoline, etc.

[0074] The ring formed by binding R¹ and R², and the “optionallysubstituted ring” represented by A in the formula above is preferably a5- to 6-membered aromatic ring, more preferably benzene, furan,thiophene, pyrrole, or pyridine (preferably, a 6-membered ring), andparticularly preferably benzene.

[0075] The ring formed by binding R¹ and R², and the ring A may havesubstituent groups, examples thereof include those similar to thesubstituent groups which may be possessed by the “benzene ring” in the“optionally substituted benzene ring” described above. 1 to 3 same ordifferent substituent groups may substitute at any position of the ringwhere substitution is possible.

[0076] In the formula above, the “divalent group” represented by X ispreferably a divalent group having 3 or more atoms in the straight-chainmoiety thereof, and, for example, any group may be employed whicheverring B in the following formula can form a 5- to 16-membered ring(preferably 5- to 12-membered ring, more preferably 7- to 10-memberedring, particularly preferably 8- to 10-membered ring): the formula

[0077] the formula

[0078] or the formula

[0079] That is, X may be any of divalent groups having 1 to 12 atoms inthe straight-chain moiety thereof (preferably 1 to 8, more preferably 3to 6, and particularly preferably 4 to 6), and specific examples of thedivalent group include

[0080] (1) —(CH₂)_(a1)— (a1 is an integer of 1 to 12, preferably 3 to12), —(CH₂)_(a2)—(CH═CH)—(CH₂)_(a3)— (a2 and a3 each are the same ordifferent integer of 0 to 10. But, the sum of a2 and a3 is 10 or lower,preferably 1 to 10), —(CH₂)_(a4)—(CH═C═CH)—(CH₂)_(a5)— (a4 and a5 eachare the same or different integer of 0 to 9. But, the sum of a4 and a5is 9 or lower),

[0081] (2) —(CH₂)_(b1)—Y—(CH₂)_(b2)— (b1 and b2 each are the same ordifferent integer of 0 to 11. But, the sum of b1 and b2 is 11 or lower,preferably 2 to 11. Y is O, S, or NH),—(CH₂)_(b3)—Y—(CH₂)_(b4)—(CH═CH)—(CH₂)_(b5)— or—(CH₂)_(b5)—(CH═CH)—(CH₂)_(b4)—Y— (CH₂)_(b3)— (b3, b4 and b5 are,respectively, the same or different integer of 0 to 9. But, the sum ofb3, b4 and b5 is 9 or less. Y is O, S, or NH),—(CH₂)_(b6)—Y—(CH₂)_(b7)—(CH═C═CH)‘(CH₂)_(b8)— or—(CH₂)_(b8)—(CH═C═CH)—(CH₂)_(b7)—Y—(CH₂)_(b6)— (b6, b7, and b8 are,respectively, the same or different integer of 0 to 8. But, the sum ofb6, b7 and b8 is 8 or less. Y is O, S, or NH),

[0082] (3) —(CH₂)_(c1)—(N═CH)—(CH₂)_(c2)— (c1 and c2 are, respectively,the same or different integer of 0 to 10. But, the sum of c1 and c2 is10 or less, preferably 1 to 10),—(CH₂)_(c3)—(N═CH)—(CH₂)_(c4)—(CH═CH)—(CH₂)_(c5)— or—(CH₂)_(c5)—CH═CH)—(CH₂)_(c4)—(N═CH)—(CH₂)_(c3)— (c3, c4 and c5 are,respectively, the same or different integer of 0 to 8. But, the sum ofc3, c4 and c5 is 8 or less),—(CH₂)_(c6)—(N═CH)—(CH₂)_(c7)—(CH═C═CH)—(CH₂)_(c8)— or—(CH₂)_(c8)—(CH═C═CH)—(CH₂)_(c7)—(N═CH)—(CH₂)_(c6)— (c6, c7 and c8 are,respectively, the same or different integer of 0 to 7. But, the sum ofc6, c7 and c8 is 7 or less),

[0083] (4) —(CH₂)_(d1)—(CH═N)—(CH₂)_(d2)— (d1 and d2 are, respectivelythe same or different integer of 0 to 10. But, the sum of d1 and d2 is10 or lower, preferably 1 to 10),—(CH₂)_(d3)—(CH═N)—(CH₂)_(d4)—(CH═CH)—(CH₂)_(d5)— or—(CH₂)_(d5)—═CH)—(CH₂)_(d4)—(CH═N)—(CH₂)_(d3)— (d3, d4 and d5 are,respectively, the same or different integer of 0 to 8. But, the sum ofd3, d4 and d5 is 8 or less),—(CH₂)_(d6)—(CH═N)—(CH₂)_(d7)—(CH═C═CH)—(CH₂)_(d8)— or—(CH₂)_(d8)—(CH═C═CH)—(CH₂)_(d7)—(CH═N)—(CH₂)_(d6)— (d6, d7 and d8 are,respectively, the same or different integer of 0 to 7. But, the sum ofd6, d7 and d8 is 7 or less),

[0084] (5) —(CH₂)_(e1)—(N═N)—(CH₂)_(e2)— (e1 and e2 are, respectively,the same or different integer of 0 to 10. But, the sum of e1 and e2 is10 or less, preferably 1 to 10),—(CH₂)_(e3)—(N═N)—(CH₂)_(e4)—(CH═CH)—(CH₂)_(e5)— or—(CH₂)_(e5)—(CH═CH)—(CH₂)_(e4)—(N═N)—(CH₂)_(e3)— (e3, e4 and e5 are,respectively, the same or different integer of 0 to 8. But, the sum ofe3, e4 and e5 is 8 or less),—(CH₂)_(e6)—(N═N)—(CH₂)_(e7)—(CH═C═CH)—(CH₂)_(e8)— or—(CH₂)_(e8)—(CH═C═CH)—(CH₂)_(e7)—(N═N)—(CH₂)_(e6)— (e6, e7 and e8 are,respectively, the same or different integer of 0 to 7. But, the sum ofe6, e7 and e8 is 7 or less),

[0085] (6) —(CH₂)_(f1)—Y—(CH₂)_(f2)—(N═CH)—(CH₂)_(f3)— (f1, f2 and f3are, respectively, the same or different integer of 0 to 9. But, the sumof f1, f2 and f3 is 9 or less. Y is O, S or NH),—(CH₂)_(f3)—(N═CH)—(CH₂)_(f2)—Y—(CH₂)_(f1)— (f1, f2 and f3 are,respectively, the same or different integer of 0 to 9. But, the sum off1, f2 and f3 is 9 or less, Y is O, S or NH),—(CH₂)_(f4)—(CH═CH)—(CH₂)_(f5)—Y—(CH₂)_(f6)—(N═CH)—(CH₂)_(f7)—(f4, f5,f6 and f7 are, respectively, the same or different integer of 0 to 7.But, the sum of f4, f5, f6 and f7 is 7 or less. Y is O, S or NH),—(CH₂)_(f8)—Y—(CH₂)_(f9)—(CH═CH)—(CH₂)_(f10)—(N═CH)—(CH₂)_(f11)— (f8,f9, f10 and f11 are, respectively, the same or different integer of 0 to7. But, the sum of f8, f9, f10 and f11 is 7 or less. Y is O, S or NH),—(CH₂)_(f12)—Y—(CH₂)_(f13)—(N═CH)—(CH₂)_(f14)—(CH═CH)—(CH₂)_(f15)— (f12,f13, f14 and f15 are, respectively, the same or different integer of 0to 7. But, the sum of f12, f13, f14 and f15 is 7 or less),—(CH₂)_(f7)—(N═CH)—(CH₂)_(f6)—Y—(CH₂)_(f15)—(CH═CH)—(CH₂)_(f4)— (f4, f5,f6 and f7 are, respectively, the same or different integer of 0 to 7.But, the sum of f4, f5, f6 and f7 is 7 or less. Y is O, S or NH),—(CH₂)_(f11)—(N═CH)—(CH₂)_(f10)—(CH═CH)—(CH₂)_(f9)—Y—(CH₂)_(f8)—(f8, f9,f10 and f11 are, respectively, the same or different integer of 0 to 7.But, the sum of f8, f9, f10 and f11 is 7 or less. Y is O, S or NH),—(CH₂)_(f15)—(CH═CH)—(CH₂)_(f14)—(N═CH)—(CH₂)_(f13)—Y—(CH₂)_(f12)— (f12,f13, f14 and f15 are, respectively, the same or different integer of 0to 7. But,the sum of f12, f13, f14 and f15 is 7 or less),

[0086] (7) —(CH₂)_(g1)—Y—(CH₂)_(g2)—(CH═N)—(CH₂)_(g3)— (g1, g2 and g3are, respectively the same or different integer of 0 to 9. But, the sumof g1, g2 and g3 is 9 or less. Y is O, S or NH),—(CH₂)_(g3)—(CH═N)—(CH₂)_(g2)—Y—(CH₂)_(g1)— (g1, g2 and g3 are,respectively, the same or different integer of 0 to 9. But, the sum ofg1, g2 and g3 is 9 or less. Y is O, S or NH),—(CH₂)_(g4)—(CH═CH)—(CH₂)_(g5)—Y—(CH₂)_(g6)—(CH═N)—(CH₂)_(g7)— (g4, g5,g6 and g7 are, respectively, the same or different integer of 0 to 7.But, the sum of g4, g5, g6 and g7 is 7 or less. Y is O, S or NH),—(CH₂)_(g8)—Y—(CH₂)_(g9)—(CH═CH)—(CH₂)_(g10)—(CH═N)—(CH₂)_(g11)— (g8,g9, g10 and g11 are, respectively, the same or different integer of 0 to7. But, the sum of g8, g9, g10 and g11 is 7 or less. Y is O, S or NH),—(CH₂)_(g12)—Y—(CH₂)_(g13)—(CH═N)—(CH₂)_(g14)—(CH═CH)—(CH₂)_(g15)— (g12,g13, g14 and g15 are, respectively, the same or different integer of 0to 7. But, the sum of g12, g13, g14 and g15 is 7 or less),—(CH₂)_(g7)—(CH═N)—(CH₂)_(g6)—Y—(CH₂)_(g5)—(CH═—CH)—(CH₂)_(g4)— (g4, g5,g6 and g7 are, respectively, the same or different integer of 0 to 7.But, the sum of g4, g5, g6 and g7 is 7 or less. Y is O, S or NH),—(CH₂)_(g11)—(CH═N)—(CH₂)_(g10)—(CH═CH)—(CH₂)_(g9)—Y—(CH₂)_(g8)—(g8, g9,g10 and g11 are, respectively, the same or different integer of 0 to 7.But, the sum of g8, g9, g10 and g11 is 7 or less. Y is O, S or NH),—(CH₂)_(g15)—(CH═CH)—(CH₂)_(g14)—(CH═N)—(CH₂)_(g13)—Y—(CH₂)_(g12)— (g12,g13, g14 and g15 are, respectively, the same or different integer of 0to 7. But, the sum of g12, g13, g14 and g15 is 7 or less),

[0087] (8) —(CH₂)_(h1)—Y—(CH₂)_(h2)—(N═N)—(CH₂)_(h3)— (h1, h2 and h3are, respectively the same or different integer of 0 to 9. But, the sumof h1, h2 and h3 is 9 or less. Y is O, S or NH), —(CH₂)_(h3)—(N═N)—(CH₂)_(h2)—Y—(CH₂)_(h1)—(h1, h2 and h3 are, respectively,the same of different integer of 0 to 9. But, the sum of h1, h2 and h3is 9 or less. Y is O, S or NH),—(CH₂)_(h4)—(CH═CH)—(CH₂)_(h5)—Y—(CH₂)_(h6)—(N═N)—(CH₂)_(h7)— (h4, h5,h6 and h7 are, respectively, the same or different integer of 0 to 7.But, the sum of h4, h5, h6 and h7 is 7 or less. Y is O, S or NH),—(CH₂)_(h8)—Y—(CH₂)_(h9)—(CH═CH)—(CH₂)_(h10)—(N═N)—(CH₂)_(h11)—(h8, h9,h10 and h11 are, respectively, the same or different integer of 0 to 7.But, the sum of h8, h9, h10 and h11 is 7 or less. Y is O, S or NH),—(CH₂)_(h12)—Y—(CH₂)_(h13)—(N═N)—(CH₂)_(h14)—(CH═CH)—(CH₂)_(h15)— (h12,h13, h14 and h15 are, respectively, the same or different integer of 0to 7. But, the sum of h12, h13, h14 and h15 is 7 or less),—(CH₂)_(h7)—(N═N)—(CH₂)_(h6)—Y—(CH₂)_(h5)—(CH═CH)—(CH₂)_(h4)— (h4, h5,h6 and h7 are, respectively, the same or different integer of 0 to 7.But, the sum of h4, h5, h6 and h7 is 7 or less. Y is O, S or NH),—(CH₂)_(h11)—(N═N)—(CH₂)_(h10)—(CH═CH)—(CH₂)_(h9)—Y—(CH₂)_(h8)— (h8, h9,h10 and h11 are, respectively the same or different integer of 0 to 7.But, the sum of h8, h9, h10 and h11 is 7 or less. Y is O, S or NH),—(CH₂)_(h15)—(CH═CH)—(CH₂ _(h14)—(N═N)—(CH₂)_(h13)—Y—(CH₂)_(h12)— (h12,h13, h14 and h15 are, respectively, the same or different integer of 0to 7. But, the sum of h12, h13, h14 and h15 is 7 or less),

[0088] (9) —(CH₂)_(j1)—Y¹—(CH₂)_(j2)—Y²—(CH₂)_(j3)— (j1, j2 and j3 are,respectively, the same or different integer of 0 to 10. But, the sum ofj1, j2 and j3 is 10 or less, preferably 1 to 10. Y¹ and y² are,respectively, O, S or NH),—(CH₂)_(j4)—Y⁴—(CH₂)_(j5)—Y⁵—(CH₂)_(j6)—Y⁶-(CH₂)_(j7)— (j4, j5, j6 andj7 are, respectively, the same or different integer of 0 to 9. But, thesum of j4, j5, j6 and j7 is 9 or lower. Y⁴, Y⁵, Y⁶ and Y⁷ are,respectively, O, S or NH), and so on. Specific examples of the divalentgroup include —O—, —O—(CH₂)_(k1)— (k1 is an integer of 1 to 5,preferably 2 to 5), —O—CH═CH—, —O—CH₂—CH═CH—, —O—CH═CH—CH₂—,—(CH₂)_(k1)—O— (k1 is an integer of 1 to 5, preferably 2 to 5),—CH═CH—O—, —CH₂—CH═CH—)—, —CH═CH—CH₂—O—, —S—, —S—(CH₂)_(k2)— (k2 is aninteger of 1 to 5, preferably 2 to 5), —S—CH═CH—, —S—CH₂—CH═CH—,—S—CH═CH—CH₂—, —(CH₂)_(k1)—S— (k1 is an integer of 1 to 5, preferably 2to 5), —CH═CH—S—, —CH₂—CH═CH—S—, —CH═CH—CH₂—S—, —NH—, —NH—(CH₂)_(k2)—(k2 is an integer of 1 to 5, preferably 2 to 5), —NH—CH═CH—,—NH—CH₂—CH═CH—, —NH—CH═CH—CH₂—, —(CH₂)_(k1)—NH— (k1 is an integer of 1to 5, preferably 2 to 5), —CH═CH—NH—, —CH₂—CH═CH—NH—, —CH═CH—CH₂—NH—,—(CH₂)_(k2)— (k2 is an integer of 1 to 5, preferably 2 to 5), —CH═CH—,—CH₂—CH═CH—, —CH═CH—CH₂—, —N═CH—, —CH═N—, —N═N—, —CH₂—N═CH—, —CH₂—CH═N—,—CH₂—N═N—, —N═CH—CH₂—, —CH═N—CH₂—, —N═N—CH₂— etc., and preferableexamples include —O—(CH₂)_(k1)— (k1 is an integer of 1 to 5, preferably2 to 5, more preferably 3 to 5), —S—(CH₂) k₂— (k2 is an integer of 1 to5, preferably 2 to 5, more preferably 3 to 5), —NH—(CH₂)_(k2)— (k2 is aninteger of 1 to 5, preferably 2 to 5, more preferably 3 to 5),—(CH₂)_(k2)— (k2 is an integer of 1 to 5, preferably 2 to 5, morepreferably 3 to 5), —(CH₂)_(k1)—O— (k1 is an integer of 1 to 5,preferably 2 to 5, more preferably 3 to 5), —(CH₂)_(k1)—S— (k1 is aninteger of 1 to 5, preferably 2 to 5, more preferably 3 to 5), and—(CH₂)_(k1)—NH— (k1 is an integer of 1 to 5, preferably 2 to 5, morepreferably 3 to 5), and more preferable examples are—O—(CH₂)₂—O—(CH₂)₃—, —O—(CH₂)₄—, —O—(CH₂)₅—,—S—(CH₂)₃—,—S—(CH₂)₄—,—S—(CH₂)₅—, —NH—(CH₂)₃—, —NH—(CH₂)₄—, —NH—(CH₂)₅— and the like.

[0089] The divalent group may have substituent groups, and saidsubstituent groups may be any group which can be bound to the divalentgroup, including, for example, a halogen atom, an optionally substitutedamino group, an optionally substituted hydroxy group, an optionallysubstituted thiol group, an optionally substituted hydrocarbon group andan optionally substituted heterocyclic group exemplified as R¹ and R².Further, the substituent groups may be bound to each other to form aring with the divalent group, and such rings include those exemplifiedas the rings formed by binding R¹ and R². Further, when an atomconstituting the straight chain moiety is a sulfur atom in the “divalentgroup” represented by X above, the sulfur atom may be oxidized, and maybe any of —S—, —SO— or —SO₂—.

[0090] Further, R¹ and a substituent group on X or R² and R³ may bebound to each other to form an optionally substituted ring, and examplesof such ring include those exemplified as the optionally substitutedrings formed by binding R¹ and R². When R¹ and a substituent group on Xare bound to each other to form an optionally substituted ring, asubstituent group on the first to third (preferably the first to second,more preferably the first) atom in the straight chain moiety of X boundto the ethylene or vinylene is preferably bound to R¹.

[0091] Alternatively, a substituent group on the “ethylene” or“vinylene” of the “optionally substituted ethylene” or “optionallysubstituted vinylene” represented by W may be bound to a substituentgroup of X or R³ to form an optionally substituted ring, and examples ofsuch ring include those exemplified as the optionally substituted ringsformed by binding R¹ and R². When a substituent group of the “ethylene”or “vinylene” and a substituent group of X are bound to each other toform a ring, binding between a substituent on the first to third(preferably first to second, more preferably first) atom in the straightchain moiety of X bound to the ethylene or vinylene and a substituentgroup of the “ethylene” or “vinylene” is preferable.

[0092] In the formula above, the combined line of “broken line and solidline” indicates a single bond or a double bond (preferably double bond).

[0093] When a compound having a substituent group is a basic compounddepending on the kind of the substituent group exemplified above, thecompound may be converted to a salt thereof by using an acid accordingto usual methods. Any acid may be used if the acid does not interferewith the reaction, and examples of the acid include inorganic acids suchas hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid,nitric acid, sulfamic acid etc., organic acids such as formic acid,acetic acid, trifluoroacetic acid, tartaric acid, citric acid, fumaricacid, maleic acid, succinic acid, malic acid, p-toluenesulfonic acid,methanesulfonic acid, benzenesulfonic acid etc., and acidic amino acidssuch as aspartic acid, glutamic acid etc. When an obtained compound is asalt, the compound may be converted to a free base according to usualmethods.

[0094] Alternatively, when a compound having a substituent group is anacidic compound depending on the kind of the substituent groupexemplified above, the compound may be converted to a salt thereof byusing a base according to usual methods. Any base may be used if thebase does not interfere with the reaction, and examples of such saltsinclude salts with inorganic bases, organic bases, basic amino acids,etc. Preferable examples of the salt with an inorganic base includealkali metal salts such as sodium salt, potassium salt, etc.;alkali-earth metal salts such as calcium salt, magnesium salt, etc.; andaluminum salt, ammonium salt, etc. Preferable examples of the salt withan organic base include salts with trimethylamine, triethylamine,pyridine, picoline, ethanolamine, diethanolamine, triethanolamine,dicyclohexylamine, N,N′-dibenzylethylenediamine, etc. Preferableexamples of the salt with a basic amino acid include salts witharginine, lysine, ornithine, etc. When an obtained compound is a salt,the compound may be converted to a free acid according to usual methods.

[0095] The reaction above-mentioned (1) is conducted, for example, undera following reaction condition.

[0096] The compound represented by the formula:

[0097] [wherein each symbol has the same meaning described above] or asalt thereof is produced by subjecting a compound represented by theformula:

[0098] [wherein each symbol has the same meaning described above] or asalt thereof to cyclization reaction in a solvent containing carbonicdiester.

[0099] The reaction above-mentioned (1) is preferably conducted in thepresence of a base, and examples of such base include metal hydridecompounds (e.g., alkali metal hydrides such as sodium hydride, potassiumhydride, etc.), metal hydrocarbons (e.g., compounds having directchemical bond between alkali metal and C₁₋₄ alkyl group such asn-butyllithium, etc.), alcoholates (e.g., compounds in which a hydroxyhydrogen of C₁₋₄ alcohols is replaced by a alkali metal such as sodiummethoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide,potassium ethoxide, potassium t-butoxide, lithium methoxide, lithiumethoxide, lithium t-butoxide, etc.), alkali metal hydroxides (e.g.,NaOH, KOH, etc.), basic carbonates (e.g., alkali metal salts ofcarbonate such as sodium salt, potassium salt, etc., or alkali-earthmetal salts of carbonate such as calcium salt, magnesium salt, etc.),basic bicarbonates (e.g., alkali metal salts of bicarbonate such assodium salt, potassium salt, etc.), and organic bases (e.g.,trimethylamine, triethylamine, diisopropylethylamine, pyridine,picoline, N-methylpyrrolidine, N-methylmorpholine,1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane,1,8-diazabicyclo [5.4.0]-7-undecene, etc.), and preferably metal hydridecompounds (e.g., sodium hydride, potassium hydride, etc.), alcoholates(e.g., NaOMe, NaOEt, t-BuONa, t-BuOK, etc.), particularly preferablyalcoholates (e.g., NaOMe, NaOEt, t-BuONa, t-BuOK, etc.) is used.

[0100] The amount of base used for the reaction above-mentioned (1) isabout 0.1 to 100 equivalents, preferably 1 to 5 equivalents.

[0101] The reaction solvent may be any solvent if only it containscarbonic diester, for example, a carbonic diester alone, a mixture of 2or more carbonic diesters or a mixed solvent of carbonic diesters and asolvent except carbonic diesters.

[0102] The carbonic diester is a compound represented by the formula,Z″—O(CO)O—Z′, [wherein, Z″ and Z′ each are an optionally substitutedhydrocarbon group (preferably an optionally substituted alkyl group)].Preferable are carbonic diesters which are liquid at the reactiontemperature. In addition, Z″ and Z′ are preferably the same, andpreferable examples of the carbonic diester are dialkyl carbonates, anddi C₁₋₄ alkyl carbonates such as dimethyl carbonate, diethyl carbonateare preferably used.

[0103] The “solvent except carbonic diesters” used in combination withone or more kinds of carbonic diesters may be any solvent if the solventdoes not interfere with the reaction, and includes, for example,halogenated solvents (e.g., methylene chloride, dichloroethane,chloroform, etc.), aliphatic hydrocarbons (e.g., n-hexane, etc.),aromatic hydrocarbons (e.g., benzene, toluene, etc.), ethers (e.g.,tetrahydrofuran (THF), diethylether, etc.), polar solvents (e.g.,dimethylformamide (DMF), dimethylsulfoxide (DMSO), etc.), alcohols(e.g., methanol, ethanol, propanol, isopropanol, n-butanol,2-methoxyethanol, etc.), formic acid esters (e.g., C₁₋₄ alkyl formate,etc.), and oxalic acid diesters (e.g., di C₁₋₄ alkyl oxalate, etc), andpreferably dimethylformamide (DMF), alcohols (e.g., methanol, ethanol,etc.) and so on.

[0104] The reaction may be conducted in an appropriate mixed solvent,preferably in a solvent containing carbonic diester (preferably,dimethyl carbonate or diethyl carbonate).

[0105] The reaction temperature is usually about −20 to 200° C.,preferably about 10 to 100° C., and the reaction period is usually about0.1 to 100 hours, preferably about 0.5 to 50 hours.

[0106] The reaction above-mentioned (7) is conducted, for example, undera following reaction condition.

[0107] The compound represented by the formula:

[0108] [wherein each symbol has the same meaning described above] or asalt thereof is produced by subjecting a compound represented by theformula:

[0109] [wherein each symbol has the same meaning described above] or asalt thereof to a cyclization reaction in a solvent containing acarbonic diester.

[0110] The reaction above-mentioned (7) may be conducted under a similarcondition to that for the reaction above-mentioned (1).

[0111] The reaction above-mentioned (13) is conducted for example undera following reaction condition.

[0112] The compound represented by the formula:

[0113] [wherein each symbol has the same meaning described above] or asalt thereof is produced by subjecting a compound represented by theformula:

[0114] [wherein each symbol has the same meaning described above] or asalt thereof to a cyclization reaction in a solvent containing acarbonic diester.

[0115] The reaction above-mentioned (13) may be conducted under acondition similar to those for the reaction above-mentioned (1).

[0116] Among the compounds represented by the following formula:

[0117] [wherein each symbol has the same meaning described above] or thesalt thereof obtained in the reaction above-mentioned (1), the compoundsrepresented by the formula:

[0118] [wherein, Z is an electron-withdrawing group, W is an optionallysubstituted ethylene or an optionally substituted vinylene and when theethylene or vinylene has two substituent groups, said substituent groupsmay be bound to each other to form an optionally substituted ring, R³ isa hydrogen atom or an optionally substituted hydrocarbon group, and X″is a divalent group having 4 or more atoms in the straight-chain moietythereof (preferably, a divalent group having 4, 5 or 6 atoms in thestraight-chain moiety thereof)] or the salts thereof are novel compoundswhich have not been described in literature.

[0119] Further, the compounds represented by the formula:

[0120] [wherein, each symbol has the same meaning described above] or asalt thereof obtained in the reaction above-mentioned (1) are useful asmedicines, agricultural chemicals, foods, cosmetics and chemicals, orintermediates therefor. For example, from the compounds represented bythe formula:

[0121] [wherein each symbol has the same meaning described above] or thesalt thereof obtained in the reaction above-mentioned (1), usefulmedicines such as an osteogenesis promoter, a Na—H exchange inhibitor,treating agent for pollakiuria and incontinence of urine, edema treatingagent and treating agent for central nervous system diseases can beproduced according to the methods known in the art (e.g., methodsdescribed in JP-A 8-73476, WO99/55690, JP-A 11-302267, JP-A 11-302270,WO99/51242, etc.).

[0122] Best Mode for Carrying Out the Invention

[0123] Hereinafter, the present invention is described in more detail bythe following Reference Examples and Examples, which are not intended torestrict the present invention.

EXAMPLES

[0124] Preparation of 2-alkoxybenzaldehyde Derivatives in General;

Reference Example 1 Ethyl 4-(2-Formylphenoxy)butyrate

[0125] Ethyl 4-bromobutyrate (6.6 ml) was added to a suspension ofsalicyl aldehyde (5.0 g) and potassium carbonate (6.2 g) in DMF(15 ml),and the mixture was stirred at 90° C. for 1 hour. The mixture wasallowed to cool to room temperature, and neutralized with 1Nhydrochloric acid. After extraction with ethyl acetate, the organiclayer was washed with saturated salt water, dried over anhydrous sodiumsulfate, and concentrated. The concentrate was purified by silica gelcolumn chromatography (n-hexane/ethyl acetate=4/1) and subsequentconcentration of the appropriate eluate gave colorless oil of Ethyl4-(2-formylphenoxy)butyrate (9.6 g, yield 99%).

[0126]¹H-NMR(CDCl₃, δ, 300 MHz): 1.27(3H, t, J=7.1 Hz), 2.14-2.23(2H,m), 2.54(2H, t, J=7.2Hz), 4.11-4.18(4H, m), 6.96-7.04(2H, m), 7.52(1H,dt, J=1.7, 7.1 Hz), 7.82(1H, dd, J=1.7, 7.7 Hz), 10.49(1H, s).

[0127] IR(neat, cm⁻¹): 1733, 1687, 1598, 1243.

[0128] Compounds below in [REFERENCE EXAMPLE 2] to [REFERENCE EXAMPLE 4]were prepared according to a method similar to that of [REFERENCEEXAMPLE 1].

Reference Example 2 Ethyl 4-(4-Bromo-2-formyl phenoxy)butyrate

[0129] Colorless oil, yield 98%. ¹H-NMR(CDCl₃, δ, 300 MHz): 1.23(3H, t,J=7.1 Hz), 2.11-2.20(2H, m), 2.50(2H, t, J=7.2 Hz), 4.08-4.16(4H, m),6.85(1H, d, J=8.9), 7.58(1H, dd, J=8.9, 2.6 Hz), 7.88(1H, d, J=2.6 Hz),10.37 (1H, s).

[0130] IR(neat, cm⁻¹): 1731, 1683, 1590, 1272.

Reference Example 3 Ethyl 4-(2-Formyl-4-methoxy phenoxy)butyrate

[0131] Colorless oil, yield 99%. ¹H-NMR(CDCl₃, δ, 300 MHz): 1.23(3H, t,J=7.1 Hz), 2.09-2.18(2H, m), 2.50(2H, t, J=7.2 Hz), 3.77(3H, s),4.05-4.15(4H, m), 6.90(1H, d, J=9.1), 7.08(1H, dd, J=9.1, 3.2 Hz),7.30(1H, d, J=3.2 Hz), 10.43(1H, s). IR(neat, cm⁻¹): 1731, 1683, 1496,1218.

Reference Example 4 Ethyl 5-(2-Formyl-4-methoxyphenoxy)pentanoate

[0132] Colorless oil, yield 99%. ¹H-NMR(CDCl₃, δ, 300 MHz): 1.21(3H, t,J=7.1 Hz), 1.80-1.87(4H, m), 2.37(2H, t, J=7.1 Hz), 3.77(3H, s),4.01-4.14(4H, m), 6.89(1H, d, J=9.1 Hz), 7.08(1H, dd, J=9.1, 3.2 Hz),7.29(1H, d, J=3.2 Hz), 10.44 (1H, s). IR(neat, cm⁻¹): 1731, 1683, 1496,1218.

[0133] Preparation of 2-formyl-N-methylaniline Derivatives in General

Reference Example 5 5-(4-Bromo-2-formyl-N-methylanilino)pentanoic acid

[0134] A suspension of 1-methyl-2-piperidone (5.0 g) in 4N sodiumhydroxide (22.1 ml) was heated and stirred for 8.5 hours under reflux.After the suspension was cooled to room temperature, conc. hydrochloricacid (7.4 ml) was added. A solution of sodium carbonate (9.4 g) and5-bromo-4-fluorobezaldehyde (4.5 g) in DMSO (74 ml) was added, and theresulting mixture was stirred for 1.5 hours under reflux. The mixturewas allowed to cool to room temperature, and adjusted to pH of about 3.3with 6N hydrochloric acid. After extraction with ethyl acetate, theorganic layer was washed with saturated salt water, dried over anhydroussodium sulfate, and concentrated. The precipitated crystal obtained wasredissolved in isopropylether [IPE] (20 ml) under heating, and thesolution was allowed to cool to room temperature, and stirred for 1 hourat 0° C. The crystal obtained was filtered and washed with IPE. Dryingunder reduced pressure (40° C., 1 hour) gave yellow crystal of5-(4-bromo-2-formyl-N-methylanilino)pentanoic acid (4.0 g, yield 57%).

[0135] mp. 72-73° C. ¹H-NMR (CDCl₃, δ, 300 MHz): 1.61-1.69(4H, m),2.36(2H, t, J=6.7 Hz), 2.87(3H, s), 3.13(2H, t, J=6.9 Hz), 6.97(1H, d,J=8.8 Hz), 7.54(1H, dd, J=8.8, 2.5 Hz), 7.86(1H, d, J=2.5 Hz), 10.17(1H,s). Anal. Calcd for C₁₃ H₁₆ NO₃ Br: C,49.70; H,5.13; N,4.46; Br,25.43,Found: C,49.75; H,5.16; N,4.45; Br,25.40. IR(KBr, cm⁻¹): 1731, 1648.

[0136] Compounds below in [REFERENCE EXAMPLE 6] to [Reference EXAMPLE 8]were prepared according to a method similar to that of [REFERENCEEXAMPLE 5].

Reference Example 6 5-(2-Formyl-N-methylanilino)pentanoic acid

[0137] Yellow oil, yield 37%. ¹H-NMR(CDCl₃, δ, 300 MHz): 1.64-1.73(4H,m), 2.38(2H, t, J=6.7 Hz), 2.90(3H, s), 3.17(2H, t, J=6.9 Hz),7.04-7.13(2H, m), 7.50(1H, dd, J=1.7, 5.5 Hz), 7.80(1H, dd, J=1.7, 7.7Hz), 10.28(1H. s).

[0138] IR(neat, cm⁻¹): 1708, 1683.

Reference Example 7 5-(2-Formyl-4-nitro-N-methylanilino)pentanoic acid

[0139] Yellow crystal, yield 93%. mp. 107-108° C. ¹H-NMR(CDCl₃, δ, 300MHz): 1.60-1.67(2H, m), 1.75-1.81(2H, m), 2.38(2H, t, J=6.7 Hz),2.90(3H, s), 3.43(2H, t, J=7.4 Hz), 6.98(1H, d, J=9.4), 8.20(1H, dd,J=9.4, 2.8 Hz), 8.58(1H, d, J=2.8 Hz), 9.67(1H, s). IR (KBr, cm⁻¹) :1704, 1677, 1598, 1324, 1307.

Reference Example 8 6-(4-Bromo-2-formyl-N-methylanilino) hexanoic acid

[0140] Yellow crystal, yield 80%. mp. 95-96° C. ¹H-NMR(CDCl₃, δ, 300MHz): 1.27-1.32(2H, m), 1.54-1.66(4H, m), 2.31(2H, t, J=7.4 Hz),2.83(3H, s), 3.08(2H, t, J=7.5 Hz), 6.93(1H, d, J=8.8 Hz), 7.50(1H, dd,J=8.8, 2.5 Hz), 7.83(1H, d, J=2.5 Hz), 10.12(1H, s). Anal. Calcd for C₁₄H₁₈ NO₃ Br: C,51.23; H,5.53; N,4.27; Br,24.35. Found: C,51.25; H,5.54;N,4.21; Br,24.48. IR (KBr, cm⁻¹): 1720, 1644.

[0141] Preparation of 2-formyl-N-benzylaniline Derivatives in General

Reference Example 9 5-(4-Bromo-2-formyl-N-benzylanilino)pentanoic acid

[0142] To a solution of benzaldehyde (6.0 g) in methanol (80 ml),4-aminobutyric acid (6.6 g) and 1N sodium hydroxide (56.5 ml) wereadded. 20% Pd—C(wet, 0.6 g) was added to the reaction apparatus whichwas previously purged with an argon gas. Subsequently, the apparatus wasfilled with a hydrogen gas, and the solution was stirred at roomtemperature overnight. Pd—C was filtered off and washed with methanol.To the filtrate was added 6N hydrochloric acid (9.4 ml), and thesolvents were evaporated. Subsequently, sodium carbonate (12.0 g) andDMSO/water (57 ml/37 ml) were added to the residue, and the resultingmixture was heated under reflux with dropwise addition of a solution of5-bromo-4-fluorobenzaldehyde (5.7 g) in DMSO (17 ml), and stirredfurther for 5 hours. After cooled to room temperature, the solution wasadjusted to pH of about 3.5 by addition of 6N hydrochloric acid. Afterextraction with ethyl acetate, the organic layer was washed withsaturated salt water, dried over anhydrous sodium sulfate, andconcentrated. The concentrate was purified by silica gel columnchromatography (n-hexane/ethyl acetate=4/1) and subsequent concentrationof the appropriate eluate gave yellow oil of5-(4-bromo-2-formyl-N-benzylanilino)pentanoic acid (7.4 g, yield 61%).

[0143]¹H-NMR(CDCl₃, δ, 300 MHz): 1.52-1.65(4H, m), 2.27-2.35(2H, m),3.08-3.15(2H, m), 4.31(2H, s), 7.01(1H, d, J=8.7 Hz), 7.16-7.36(5H, m),7.57(1H, dd, J=8.7, 2.4Hz), 7.92(1H, d, J=2.4 Hz), 10.36(1H, s).EI-MS(M⁺): 391.

[0144] IR(neat, cm⁻¹): 1708, 1683.

[0145] A compound below in [REFERENCE EXAMPLE 10] was prepared accordingto a method similar to that of [REFERENCE EXAMPLE 9].

Reference Example 10 5-(4-Bromo-2-formyl-N-benzylanilino)heptanoic acid

[0146] Yellow oil, yield 27%. ¹H-NMR(CDCl₃, δ, 300 MHz): 1.21-1.26(4H,m), 1.46-1.56(4H, m), 2.27(2H, t, J=7.4 Hz), 3.05(2H, t, J=7.5 Hz),4.26(2H, s), 6.97(1H, d, J=8.7 Hz), 7.13-7.28(5H, m), 7.51(1H, dd,J=8.7, 2.5 Hz), 7.87(1H, d, J=2.5 Hz), 10.30(1H, s). IR (neat, cm⁻¹):1706, 1683.

[0147] Cyclization Reactions in General (Method A)

Example 1 2,3-Dihydro-1-benzoxepin-4-carboxylic acid ethylester

[0148] To a solution of 4-(2-formylphenoxy)butyric acid ethylester (2.4g) in diethyl carbonate (24 ml), a solution of 20% sodium ethoxide inethanol (4.1 g) was added at room temperature, and the solution wasstirred at 50° C. for 1 hour. The solution was allowed to cool to roomtemperature, and neutralized with 1N hydrochloric acid. After ethylacetate extraction, the organic layer was washed with saturated saltwater, dried over anhydrous sodium sulfate, and concentrated. Theconcentrate was purified by silica gel column chromatography(n-hexane/ethyl acetate=10/1) and concentration of the appropriateeluate gave colorless oil of 2,3-dihydro-1-benzoxepin-4-carboxylic acidethylester (1.3 g, yield 61%).

[0149]¹H-NMR(CDCl₃, δ, 300 MHz): 1.36(3H, t, J=7.1 Hz), 2.97-3.00(2H,m), 4.26-4.31(4H, m), 6.96-7.04(2H, m), 7.21-7.27(1H, m), 7.32-7.35(1H,m), 7.58(1H, s). IR (neat, cm⁻¹): 1700, 1249.

Reference Example 11 2,3-Dihydro-1-benzoxepin-4-carboxylic acidethylester

[0150] To a solution of 4-(2-formylphenoxy)butyric acid ethylester (2.4g) in THF (24 ml), potassium t-butoxide (1.2 g) was added at roomtemperature, and the mixture was stirred at 50° C. for 2 hours. Thesolution was allowed to cool to room temperature, and neutralized with1N hydrochloric acid. After ethyl acetate extraction, the organic layerwas washed with saturated salt water. The organic layer was subjected toHPLC analysis.

[0151] The results of quantitative analyses: 4-(2-formylphenoxy)butyricacid ethylester (0.1 g, yield 4%), 4-(2-formylphenoxy)butyric acid (0.3g, yield 14%), 2,3-dihydro-1-benzoxepin-4-carboxylic acid ethylester(0.4 g, yield 17%), 2,3-dihydro-1-benzoxepin-4-carboxylic acid (0.3 g,yield 15%).

[0152] Compounds below in [EXAMPLE 2] to [EXAMPLE 4] were preparedaccording to a method similar to that of [EXAMPLE 1].

Example 2 7-Bromo-2,3-dihydro-1-benzoxepin-4-carboxylic acid ethylester(Method A)

[0153] White crystal, yield 34%. mp. 85-86° C. ¹H-NMR(CDCl₃, δ, 300MHz): 1.34(3H, t, J=7.1 Hz), 2.92-2.97(2H, m), 4.19-4.25(4H, m),6.82(1H, d, J=8.6 Hz), 7.28(1H, dd, J=8.6, 2.4 Hz), 7.42(1H, d, J=2.4Hz), 7.43(1H, s).

Example 3 7-Methoxy-2,3-dihydro-1-benzoxepin-4-carboxylic acidethylester (Method A)

[0154] White crystal, yield 82%. mp. 62-63° C. ¹H-NMR(CDCl₃, δ, 300MHz): 1.32(3H, t, J=7.1 Hz), 2.92-2.95(2H, m), 3.76(3H, s),4.17-4.28(4H, m), 6.77-6.81(2H, m), 6.87(1H, dd, J=1.6, 7.4 Hz),7.49(1H, s).

Example 4 8-Methoxy-3,4-dihydro-2H-1-benzoxocin-5-carboxylic acidethylester (Method A)

[0155] Colorless oil, yield 11%. ¹H-NMR(CDCl₃, δ, 300 MHz): 1.44(3H, t,J=7.1 Hz), 1.82-1.88(2H, m), 2.66-2.70(2H, m), 3.86(3H, s),4.24-4.39(4H, m), 6.77 (1H, d, J=3.0 Hz), 6.92(1H, dd, J=3.0, 8.9 Hz),7.02(1H, d, J=8.9 Hz), 7.70(1H, s). IR (neat, cm⁻¹): 1704, 1496, 1243.

[0156] Cyclization Reactions in General (Method B)

Example 5 8-Bromo-1-methyl-1,2,3,4-tetrahydro-1-benzazocin-5-carboxylicacid methylester

[0157] To a solution of 5-(4-bromo-2-formyl-N-methylanilino)pentanoicacid (3.0 g) in DMF(8 ml), potassium carbonate (1.6 g) and a solution ofmethyl iodide/DMF (1.6 g/2 ml) were added at room temperature, and theresulting mixture was stirred for 2 hours. Ethyl acetate and water wereadded to the mixture, and the organic layer was separated, washed withwater, dried over anhydrous sodium sulfate, and concentrated to giveyellow oil of 5-(4-bromo-2-formyl -N-methylanilino)pentanoic acidmethylester (3.0 g, yield 97%).

[0158]¹H-NMR(CDCl₃, δ, 300 MHz): 1.58-1.64(4H, m), 2.28(2H, t, J=6.8Hz), 2.83(3H, s), 3.09(2H, t, J=6.8 Hz), 3.63(3H, s), 6.95(1H, d, J=8.8Hz), 7.51(1H, dd, J=8.8, 2.4 Hz), 7,83(1H, d, J=2.4 Hz), 10.14(1H, s).FAB-MS ([M+Na]⁺): 350. IR(neat, cm⁻¹): 1735, 1681.

[0159] To a solution of 5-(4-bromo-2-formyl-N-methylanilino)pentanoicacid methylester (3.0 g) in dimethyl carbonate (40 ml), a solution of28% sodium methoxide in methanol (2.3 g) was added at room temperature,and the resulting mixture was stirred at 50° C. for 2 hours. The mixturewas allowed to cool to room temperature, and neutralized with 1Nhydrochloric acid. After ethyl acetate extraction, the organic layer waswashed with saturated salt water, dried over anhydrous sodium sulfate,and concentrated. The concentrate was purified by silica gel columnchromatography (h-hexane/ethyl acetate=10/1) and the appropriate eluatewas concentrated. The precipitated crystal was washed with IPE andcollected by filtration. Drying under reduced pressure (40° C., 1 hour)gave yellow crystal of8-bromo-1-methyl-1,2,3,4-tetrahydro-1-benzazocin-5-carboxylic acidmethylester (0.9 g, yield 31%).

[0160] mp. 88-89° C. ¹H-NMR(CDCl₃, δ, 300 MHz): 1.44(2H, m), 2.54(2H, t,J=6.2 Hz), 2.87(3H, s), 3.42(2H, t, J=5.6 Hz), 3.78(3H, s), 6.56(1H, d,J=6.0 Hz), 7.19-7.23(2H, m), 7.68(1H, s). Anal. Calcd for C₁₄ H₁₆ NO₂Br: C,54.21; H,5.20; N,4.52; Br,25.76. Found: C,54.19; H,5.29; N,4.37;Br,25.74. IR(KBr, cm⁻¹): 1689, 1189.

[0161] Compounds below in [EXAMPLE 6] to [EXAMPLE 9] were preparedaccording to a method similar to that of [EXAMPLE 5].

Example 6 1-Methyl-1,2,3,4-tetrahydro-1-benzazocin-5-carboxylic acidmethylester (Method B)

[0162] 5-(2-Formyl-N-methylanilino)pentanoic acid methylester

[0163] Yellow oil, yield 99%. ¹H-NMR(CDCl₃, δ, 300 MHz): 1.58-1.68(4H,m), 2.30(2H, t, J=6.8), 2.86(3H, s), 3.12(2H, t, J=6.8 Hz), 3.64(3H, s),7.01-7.10(2H, m), 7.46(1H, dt, J=1.7, 7.3 Hz), 7.76(1H, dd, J=1.7, 7.7Hz), 10.25(1H, s).

[0164] IR (neat, cm⁻¹): 1735, 1685, 1159.

[0165] 1-methyl-1,2,3,4-tetrahydro-l-benzazocin-5-carboxylic acidmethylester

[0166] Yellow crystal, yield 30%. mp. 80-82° C. ¹H-NMR(CDCl₃, δ, 300MHz): 1.42-1.50(2H, m), 2.57(2H, t, J=6.2 Hz), 2.90(3H, s), 3.45(2H, t,J=5.4 Hz), 3.79(3H, s), 6.62-6.73(2H, m), 7.11-7.22(2H, m), 7.80(1H, s).Anal. Calcd for C1₄ H₁₇ NO₂: C,72.70; H,7.41; N,6.06. Found: C,73.00;H,7.65; N,6.06.

[0167] IR (KBr, cm⁻¹): 1685, 1189.

Example 7 1-Benzyl-8-bromo-1,2,3,4-tetrahydro-1-benzazocin-5-carboxylicacid methylester (Method B)

[0168] 5-(4-Bromo-2-formyl-N-benzylanilino)pentanoic acid methylester

[0169] Yellow oil, yield 100%. ¹H-NMR(CDCl₃, δ, 300 MHz): 1.57-1.60(4H,m), 2.27(2H, t, J=6.7), 3.12(2H, t, J=6.6 Hz), 3.66(3H, s), 4.31(2H, s),7.01(1H, d, J=8.7), 7.17-7.33(5H, m), 7.56(1H, dd, J=8.7, 2.5 Hz),7.92(1H, d, J=2.5 Hz), 10.35 (1H,s). EI-MS (M⁺): 403. IR (neat, cm⁻¹):1735, 1683.

[0170] 1-Benzyl-8-bromo-1,2,3,4-tetrahydro-1-benzazocin-5-carboxylicacid methylester

[0171] Yellow oil, yield 76%. ¹H-NMR(CDCl₃, δ, 300 MHz): 1.44-1.50(2H,m), 2.59(2H, t, J=6.1 Hz), 3.50(2H, t, J=5.3 Hz), 3.81(3H, s), 4.45(2H,s), 6.50(1H, d, J=9.0), 7.09-7.39(7H, m), 7.75(1H, s). EI-MS(M⁺) : 385.

[0172] IR(neat, cm⁻¹): 1704, 1495, 1087.

Example 89-Bromo-1-methyl-2,3,4,5-tetrahydro-1H-1-benzazonin-6-carboxylic acidmethylester (Method B)

[0173] 6-(4-Bromo-2-formyl-N-methylanilino) hexanoic acid methylester

[0174] Yellow oil, yield 98%. ¹H-NMR(CDCl₃, δ, 300 MHz): 1.20-1.30(2H,m), 1.51-1.61(4H, m), 2.24(2H, t, J=7,4), 2.81(3H, s), 3.05(2H, t, J=6.6Hz), 3.61(3H, s), 6.91(1H, d, J=8.8 Hz), 7.47(1H, dd, J=8.8, 2.3 Hz),7.80(1H, d, J=2.3 Hz), 10.10(1H, s). FAB-MS([M+Na]⁺): 364. IR(neat,cm⁻¹): 1735, 1681.

[0175] 9-Bromo-1-methyl-2,3,4,5-tetrahydro-1H-1-benzazonin-6-carboxylicacid methylester

[0176] Yellow oil, yield 18%. ¹H-NMR-(CDCl₃, δ, 300 MHz): 1.67-1.77(2H,m), 1.87-1.96(2H, m), 2.30(2H, t, J=6.9 Hz), 2.76(3H, s), 3.12(2H, t,J=6.9 Hz), 3.77(3H, s), 6.70(1H, d, J=6.4 Hz), 7.19-7.22(2H, m),7.60(1H, s). EI-MS(M⁺): 323.

[0177] IR(neat, cm⁻¹): 1708, 1494.

[0178] Cyclization Reactions in General (Method C)

Example 9 8-Nitro-1-methyl-1,2,3,4-tetrahydro-1-benzazocin-5-carboxylicacid methylester

[0179] To a solution of 5-(2-formyl-4-nitro-N-methylanilino)pentanoicacid (3.0 g) in DMF (8.1 ml), potassium carbonate (1.6 g) and a solutionof methyl iodide/DMF (1.8 g/1 ml) were added at room temperature, andthe resulting mixture was stirred further for 2 hours. To the mixture,dimethyl carbonate (18 ml) and subsequently a solution of 28% sodiummethoxide in methanol (5.0 g) were added and the resulting mixture wasstirred at 50° C. for 2.5 hours. The mixture was allowed to cool to roomtemperature, and neutralized with 1N hydrochloric acid. After ethylacetate extraction, the organic layer was washed with saturated saltwater, dried over anhydrous sodium sulfate, and concentrated. Theconcentrate was redissolved in hot isopropyl alcohol [IPA], and thesolution was allowed to cool to room temperature, stirred at roomtemperature further for 1 hour, and at ice temperature for 0.5 hours.The precipitated crystal was collected by filtration, and washed withIPA. The crystal was purified by silica gel column chromatography(n-hexane/ethyl acetate=2/1 to 1/1), and subsequent concentration of theappropriate eluate gave yellow crystal of8-nitro-1-methyl-1,2,3,4-tetrahydro-1-benzazocin-5-carboxylic acidmethylester (2.3 g, yield 78%).

[0180] mp. 127-129° C. ¹H-NMR(CDCl₃, δ, 300 MHz): 1.38-1.72(2H, m),2.35-2.80(2H, m), 3.02(3H, s), 3.42-3.85(2H, m), 3.80(3H, s), 6.65(1H,d, J=9.4 Hz), 7.80(1H, s), 7.99-8.06(2H,m). Anal. Calcd for C₁₄ H₁₆N₂O₂: C,60.86; H,5.84; N,10.14. Found: C,60.79; H,5.81; N,9.98. IR (KBr,cm⁻¹): 1708, 1255, 1191.

[0181] A compound below in [EXAMPLE 10] was prepared according to amethod similar to that of [EXAMPLE 9].

Example 101-Benzyl-10-bromo-1,2,3,4,5,6-hexahydro-1-benzazecin-7-carboxylic acidmethylester (Method C)

[0182] Yellow oil, yield 6%. ¹H-NMR(CDCl₃, δ, 300 MHz): 1.24-1.29(2H,m), 1.44-1.50(2H, m), 1.57-1.63(2H, m), 2.13(2H, t, J=6.5 Hz), 2.89(2H,t, J=6.2 Hz), 3.48(3H, s), 3.90(2H, s), 7.02(1H, d, J=8.6 Hz),7.10-7.25(6H, m), 7.37(1H, dd, J=8.6, 2.4 Hz), 7.48(1H, s). IR(KBr,cm⁻¹): 1712, 1279, 1232.

Reference Example 11

[0183] Preparation of 4′-ethoxy-4-hydroxy-l,1′-biphenyl-3-carbaldehyde

[0184] To a suspension of magnesium (0.5 g) in THF (7 ml), a solution of1-bromo-4-ethoxybenzene (4.0 g) in THF (2.5 ml) was added slowly at roomtemperature under an argon atmosphere, and the resulting solution wasstirred for 1 hour. Subsequently, a solution of trimethoxyborane (2.1 g)in THF (2.5 ml) was added dropwise at −10 to 10° C., and after furtheraddition of THF (7 ml), the reaction mixture was stirred at the sametemperature for 1 hour. The reaction mixture was allowed to warm to roomtemperature and tetrakistriphenylphosphine palladium (115mg),5-bromo-2-hydroxybenzaldehyde (2.0 g) and an aqueous solution oftripotassium phosphate (11.1 g) in water (15 ml) were added, and theresulting mixture was stirred under reflux for 1 hour. After the mixturewas allowed to cool to room temperature, 6N hydrochloric acid (20 ml)was added dropwise, and then toluene(20 ml) was added. After separation,the aqueous phase was further extracted with toluene (30 ml). Theorganic layers were combined and washed with aqueous 10% sodium chloridesolutions (10 ml×3), dried over anhydrous magnesium sulfate andconcentrated. The concentrate was purified by silica gel chromatography(n-hexane/ethyl acetate=6/1), and the appropriate eluate wasconcentrated. Diisopropylether (15 ml) was added to the concentrate andthe resulting mixture was heated under reflux, and then allowed to coolto room temperature. n-Hexane (15 ml) was added to the solution, andstirred at room temperature for 1 hour and at 0° C. for 0.5 hour. Theprecipitated crystal was collected by filtration and washed withdiisopropylether/n-hexane (1/1.4 ml) which was previously cooled to 0 to5° C. Drying under reduced pressure (room temperature, 2 hours) gaveyellow crystal of the title compound (1.8 g, yield 73%).

[0185] mp. 94-95° C.

[0186] Anal Calcd. for C₁₅ H₁₄ O₃: C,74.36; H,5.82. Found: C,74.61;H,5.80.

[0187] IR(KBr, cm⁻¹): 1660, 1473, 1276, 1245, 1047, 831.

[0188]¹H-NMR(CDCl₃, 300 MHz) δ 1.44(3H, t, J=7.0 Hz), 4.07(2H, q, J=7.0Hz), 6.96(2H, dd, J=1.9, 6.7 Hz), 7.04(1H, d, J=8.4 Hz), 7.45(2H, dd,J=1.9, 6.7 Hz), 7.68-7.77(2H, m), 9.95(1H, s), 10.95(1H, s).

Reference Example 12

[0189] Preparation of4-[(4′-ethoxy-3-formyl-1,1′-biphenyl-4-yl)oxy]butyric acid ethylester

[0190] To a solution of4′-ethoxy-4-hydroxy-1,1′-biphyenyl-3-carbaldehyde(1.0 g), and4-bromobutyric acid ethylester (0.9 g) in DMF (5 ml) was added potassiumcarbonate (1.1 g) at room temperature, and the solution was stirred atroom temperature for 14 hours, and at 50° C. for 3 hours. After thesolution was allowed to cool to room temperature, water (10 ml) wasadded, and extracted with ethyl acetate (30 ml). The organic layer waswashed with water (10 ml×3), and concentrated. To the concentrate wasadded diisopropylether (14 ml), and the resulting mixture was heatedunder reflux and subsequently cooled to room temperature. The solutionwas further stirred at room temperature for 1 hour, and at 0° C. for 1hour. The precipitated crystal was collected by filtration and washedwith diisopropylether (3 ml) which was previously cooled to 0 to 5° C.Drying under vacuum (room temperature, 2 hours) gave white crystal ofthe title compound (1.3 g, yield 91%).

[0191] mp. 69-70° C.

[0192] Anal Calcd. for C₂₁ H₂₄ O₅: C,70.77; H,6.79. Found: C,70.91;H,7.08.

[0193] IR (KBr, cm⁻¹) 1683, 1606, 1471, 1270, 1240, 1187, 1047.

[0194]¹H-NMR(CDCl₃, 300 MHz) δ 1.26(3H, t, J=7.1 Hz), 1.43(3H, t, J=7.0Hz), 2.18-2.25(2H, m), 2.56(2H, t, J=7.1 Hz), 4.04-4.20(6H, m), 6.94(2H,dd, J=1.9, 6.7 Hz), 7.03(1H, d, J=8.7 Hz), 7.47(2H, dd, J=1.9, 6.7 Hz),7.72(1H, dd, J=8.7, 2.5 Hz), 8.02(1H, d, J=2.5 Hz), 10.53(1H, s).

Example 11

[0195] 7-(4-Ethoxyphenyl)-2,3-dihydro-1-benzoxepin-4-carboxylic acidethylester

[0196] To a solution of4-[(4′-ethoxy-3-formyl-1,1′-biphenyl-4-yl)oxy]butyric acid ethylester(0.50 g) in diethyl carbonate (5 ml) was added a solution of 20% sodiumethoxide in ethanol (0.57 g) at room temperature, and the mixture wasthen heated to 50° C. and stirred for 1 hour. The solution wasneutralized with 1N hydrochloric acid, and extracted with ethyl acetate.The organic layer was washed, and concentrated. The concentrate waspurified by silica gel chromatography (n-hexane/ethyl acetate=10/1) andsubsequent concentration of the appropriate eluate gave white crystal ofthe title compound (0.39 g, yield 82%).

[0197] mp. 128-129° C. Anal Calcd. for C₂₁ H₂₂ O₄: C,74.54; H,6.55.

[0198] Found: C,74.32; H,6.46.

[0199] IR(KBr, cm⁻¹), 1702, 1496, 1251, 1213.

[0200]¹H-NMR(CDCl₃, 300 MHz) δ 1.37(3H, t, J=7.1 Hz), 1.44(3H, t, J=7.0Hz), 2.99-3.02(2H, m), 4.07(2H, q, J=7.0 Hz), 4.26-4.32(4H, m), 6.95(2H,dd, J=1.9, 6.7 Hz), 7.00(1H, d, J=8.4 Hz), 7.41-7.51(4H, m), 7.65(1H,s).

[0201] Industrial Applicability

[0202] The present invention provides a process suitable for massproduction wherein cyclic compounds can be produced safely through ashort step.

1. A process for producing a compound represented by the formula:

[wherein, Z is an electron-withdrawing group; W is an optionallysubstituted ethylene or an optionally substituted vinylene, and when theethylene or the vinylene has two substituent groups, said substituentgroups may be bound to each other to form an optionally substitutedring; R³ is a hydrogen atom or an optionally substituted hydrocarbongroup; and X is a divalent group(however, when W is an optionallysubstituted vinylene, —X—CH₂—Z is not —X¹—X²—CH₂—Z (wherein, X¹ is asulfur atom or an optionally substituted nitrogen atom; X² is anoptionally substituted ethylene))] or a salt thereof, which comprisessubjecting a compound represented by the formula:

[wherein, each symbol has the same meaning described as above] or a saltthereof to a cyclization reaction in a solvent containing a carbonicdiester.
 2. The process according to claim 1, wherein X is a divalentgroup having 1 to 12 atoms in the straight-chain moiety thereof.
 3. Theprocess according to claim 1, wherein Z is a carboxyl group which isesterified.
 4. A process according to claim 1, wherein R³ is a hydrogenatom.
 5. A process according to claim 1, which comprises the reactionbeing carried out in the presence of a base.
 6. A process according toclaim 5, wherein the base is an alcoholate.
 7. A process for producing acompound represented by the formula:

[wherein, z is an electron-withdrawing group; R¹ and R² each are ahydrogen atom, a halogen atom, an optionally substituted amino group, anoptionally substituted hydroxy group, an optionally substituted thiolgroup, an optionally substituted hydrocarbon group or an optionallysubstituted heterocyclic group; R¹ and R² may be bound to each other toform an optionally substituted ring; R³ is a hydrogen atom or anoptionally substituted hydrocarbon group; the combined line of a brokenline and a solid line is a single bond or a double bond; and X is adivalent group (however, when the combined line of a broken line and asolid line is a double bond, —X—CH₂—Z is not —X¹—X²—CH₂—Z (wherein, X¹is a sulfur atom or an optionally substituted nitrogen atom, X² is anoptionally substituted ethylene))] or a salt thereof, which comprisessubjecting a compound represented by the formula:

[wherein, each symbol has the same meaning described as above] or a saltthereof to a cyclization reaction in a solvent containing a carbonicdiester.
 8. The process according to claim 7, wherein X is a divalentgroup having 1 to 12 atoms in the straight-chain moiety thereof.
 9. Theprocess according to claim 7, wherein Z is a carboxyl group which isesterified.
 10. The process according to claim 7, wherein R³ is ahydrogen atom.
 11. The process according to claim 7, which comprises thereaction being carried out in the presence of a base.
 12. The processaccording to claim 11, wherein the base is an alcoholate.
 13. A processfor producing a compound represented by the formula:

[wherein, Z is an electron-withdrawing group; R³ is a hydrogen atom oran optionally substituted hydrocarbon group; the combined line of abroken line and a solid line is a single bond or a double bond; ring Ais an optionally substituted ring; and X is a divalent group (however,when the ring A is an optionally substituted benzene ring and thecombined line of a broken line and a solid line is a double bond,—X—CH₂—Z is not —X¹—X²—CH₂—Z ( wherein, X¹ is sulfur atom or anoptionally substituted nitrogen atom ; X² is an optionally substitutedethylene))] or a salt thereof, which comprises subjecting a compoundrepresented by the formula:

[wherein, each symbol has the same meaning described as above] or a saltthereof to a cyclization reaction in a solvent containing a carbonicdiester.
 14. The process according to claim 13, wherein X is a divalentgroup having 1 to 12 atoms in the straight-chain moiety thereof.
 15. Theprocess according to claim 13, wherein Z is a carboxyl group which isesterified.
 16. The process according to claim 13, wherein R³ is ahydrogen atom.
 17. The process according to claim 13, which comprisesthe reaction being carried out in the presence of a base.
 18. Theprocess according to claim 17, wherein the base is an alcoholate.
 19. Acompound represented by the formula: [formula]

[wherein, Z is an electron-withdrawing group; W is an optionallysubstituted ethylene or an optionally substituted vinylene and when theethylene or the vinylene has two substituent groups, said substituentgroups may be bound to each other to form an optionally substitutedring; R³ is a hydrogen atom or an optionally substituted hydrocarbongroup; and X″ is a divalent group having 4 or more atoms in thestraight-chain moiety thereof] or a salt thereof.